N-cadherin: A diagnostic marker to help discriminate primary liver carcinomas from extrahepatic carcinomas.

Distinguishing primary liver cancer (PLC), namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), from liver metastases is of crucial clinical importance. Histopathology remains the gold standard, but differential diagnosis may be challenging. While absent in most epithelial, the expression of the adherens junction glycoprotein N-cadherin is commonly restricted to neural and mesenchymal cells, or carcinoma cells that undergo the phenomenon of epithelial-to-mesenchymal transition (EMT). However, we recently established N- and E-cadherin expression as hallmarks of normal hepatocytes and cholangiocytes, which are also preserved in HCC and iCCA. Therefore, we hypothesized that E- and/or N-cadherin may distinguish between carcinoma derived from the liver vs carcinoma of other origins. We comprehensively evaluated E- and N-cadherin in 3359 different tumors in a multicenter study using immunohistochemistry and compared our results with previously published 882 cases of PLC, including 570 HCC and 312 iCCA. Most carcinomas showed strong positivity for E-cadherin. Strong N-cadherin positivity was present in HCC and iCCA. However, except for clear cell renal cell carcinoma (23.6% of cases) and thyroid cancer (29.2%), N-cadherin was only in some instances faintly expressed in adenocarcinomas of the gastrointestinal tract (0%-0.5%), lung (7.1%), pancreas (3.9%), gynecological organs (0%-7.4%), breast (2.2%) as well as in urothelial (9.4%) and squamous cell carcinoma (0%-5.6%). As expected, N-cadherin was detected in neuroendocrine tumors (25%-75%), malignant melanoma (46.2%) and malignant mesothelioma (41%). In conclusion, N-cadherin is a useful marker for the distinction of PLC vs liver metastases of extrahepatic carcinomas (P < .01).

Carcinoma of unknown primary (CUP): an update for histopathologists.

Carcinoma of unknown primary (CUP) is a heterogeneous group of metastatic cancers in which the site of origin is not identifiable. These carcinomas have a poor outcome due to their late presentation with metastatic disease, difficulty in identifying the origin and delay in treatment. The aim of the pathologist is to broadly classify and subtype the cancer and, where possible, to confirm the likely primary site as this information best predicts patient outcome and guides treatment. In this review, we provide histopathologists with diagnostic practice points which contribute to identifying the primary origin in such cases. We present the current clinical evaluation and management from the point of view of the oncologist. We discuss the role of the pathologist in the diagnostic pathway including the control of pre-analytical conditions, assessment of sample adequacy, diagnosis of cancer including diagnostic pitfalls, and evaluation of prognostic and predictive markers. An integrated diagnostic report is ideal in cases of CUP, with results discussed at a forum such as a molecular tumour board and matched with targeted treatment. This highly specialized evolving area ultimately leads to personalized oncology and potentially improved outcomes for patients.

Primary Tumour Detection in Carcinoma of Unknown Primary with Transoral Robotic Surgery (TORS) Tongue Base Mucosectomy: A Meta-analysis.

BACKGROUND: Head and neck carcinoma of unknown primary (CUP) represents a challenging diagnostic process when standard work-up fails to identify the primary tumour site. The aim of this systematic review and meta-analysis was to evaluate the diagnostic utility and complication profile of transoral robotic surgery (TORS) tongue base mucosectomy (TBM) in the management of CUP. PATIENTS AND METHODS: An electronic database search was performed in the EMBASE, MEDLINE, PubMed and Cochrane databases. A meta-analysis of proportions was performed to obtain an estimate of the overall proportion for the detection and complication rates. RESULTS: Nine studies representing 235 patients with CUP who had TORS TBM were included in the final analysis. The overall pooled tumour detection rate was 66.2% [95% confidence interval (CI) 56.1-75.8]. The incidence of tumour detection in human papilloma virus (HPV)-positive cases (81.5%, 95% CI 60.8-96.4) was significantly higher than HPV-negative cases (2.3%, 95% CI 0.00-45.7). Weighted overall complication rate was 11.4% (95% CI 7.2-16.2). The majority were grade I or II (80%) according to the Clavien-Dindo classification. CONCLUSIONS: This meta-analysis suggests TORS to be safe and effective in localising the primary tumour site in patients with CUP. While the current data supports the use of TORS in patients who are HPV positive, larger numbers of HPV-negative cases are required to determine the true diagnostic effect with TORS before any valid conclusions can be inferred in this particular subgroup. Further research should focus on high quality prospective trials with stringent methodological work-up to minimise heterogeneity and allow for more accurate statistical analysis.

Morphologic Heterogeneity of Carcinoma with Signet Ring Cell Features at Different Primary Sites.

INTRODUCTION: Signet ring cells (SRCs) may be observed in carcinomas from multiple primary sites. Elucidating unknown primaries from metastases with SRCs represents a diagnostic challenge. This study examined morphologic characteristics of adenocarcinomas with SRCs from stablished primary sites and described objective features, which can aid in identifying the site of origin. METHODS: The series encompasses 257 cases of adenocarcinomas with SRCs from gastroesophageal junction (GEJ, n = 38), stomach (n = 48), pancreatobiliary system (n = 16), colorectum (n = 40), appendix (n = 32), breast (n = 41), and lung (n = 42). H&E sections were examined and scored using architectural and cytologic criteria. Morphometric analysis was performed using QuPath software. RESULTS: Extracellular mucin was more abundant in GEJ, colorectal, and appendiceal carcinomas. Poorly cohesive morphology was the most frequent pattern in gastric and breast carcinomas. The cytoplasmic mucin/vacuole was predominantly clear and targetoid in breast carcinomas. Breast and gastric carcinomas showed the highest nuclear to cytoplasmic (N/C) ratio, whereas appendiceal carcinoma the lowest. CONCLUSION: Morphological evaluation (extracellular mucin, architectural patterns, and the nature of cytoplasmic mucin/vacuole) represents an important step to determine the cancer site of origin in adenocarcinomas with SRCs and guides further ancillary studies. Cytological morphometry may help further refine morphological criteria and facilitate the construction of digital-pathology algorithms.

Indications for oropharyngeal biopsy in head and neck squamous cell carcinoma of unknown primary: A systematic review (HNSCCUP).

INTRODUCTION: Patients presenting with head and neck squamous cell carcinoma of unknown primary (HNSCCUP) remain challenging clinical scenarios as large variation exists in practices used to locate the primary. OBJECTIVE: The objective of this systematic review is to review of the literature and offer recommendations for oropharyngeal biopsies in HNSCCUP. METHOD: Pubmed, Medline and Embase were searched to identify studies from inception to October 2021. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. RESULTS: A total of 483 articles were included and screened, 41 studies met the inclusion criteria, including over 3400 patients from the original articles (122 of these patients were reported on in two sequential articles by a single author - table 1) and 4 large metaanalyses including 1852 patients. The primary site identification rate following random biopsies or deep tissue biopsies is less than 5% in most studies. The mean detection rate following ipsilateral tonsillectomy is 34%; two pooled analyses indicate that the mean detection rate following tongue base mucosectomy is 64%, with this figure rising when the tonsils are negative. CONCLUSIONS: High level evidence is lacking, with heterogeneity in the reported studies. Published meta-analyses are based on retrospective data. There is little evidence supporting the practice of random/non-directed oropharyngeal biopsies. Available evidence supports palatine tonsillectomy and tongue base mucosectomy compared to deep tissue biopsies.

Long-term results of radio(chemo)therapy in metastatic carcinoma to cervical lymph nodes from an unknown primary. Adult Comorbidity Evaluation 27 score as a predictor of survival.

PURPOSE: To evaluate the effectiveness and toxicity of curative (chemo)radiotherapy in patients with metastatic carcinoma to cervical lymph nodes from an unknown primary. METHODS: Retrospective study of 90 consecutive patients, treated with curative radiotherapy from 2003 to 2018 (median age 59 years; current/former smokers 76%) was conducted. The distribution of nodal staging was as follows: N1: 12%, N2a: 21%, N2b: 43%, N2c: 10%, N3: 13%. In 62% of patients, neck dissection was performed before radiotherapy. Concomitant chemotherapy was given to 64% of patients. RESULTS: The median follow-up of surviving patients was 86 months. The median total radiotherapy dose achieved was 70 Gy. The 5­ and 10-year locoregional control were 84% in both cases, while 5­ and 10-year distant control were 90% and 89%, respectively. A primary tumor in the head and neck area was detected in only 2 patients. No patient had an initial failure in the pharyngeal axis or contralateral cervical nodes. The 5­ and 10-year overall survival were 55% and 42%, respectively. Severe early toxicity occurred in 71%; severe late toxicity in 33% of patients. Multivariate analysis demonstrated N­status (hazard ratio [HR] 2.424; 95% confidence interval [CI] 1.121-5.241; p = 0.024) and comorbidity scores assessed by ACE-27 (Adult Comorbidity Evaluation; HR 3.058; 95% CI 1.489-6.281; p = 0.002) as two independent prognostic factors for overall survival. CONCLUSION: The results of our work study demonstrate the high effectiveness of curative (chemo)radiotherapy on the pharyngeal axis and bilateral cervical nodes with long-term locoregional and distant control in 3/4 of the treated patients. N­status and comorbidity scores were shown as strong prognostic factors influencing overall survival.

Contemporary Imaging and Reporting Strategies for Head and Neck Cancer: MRI, FDG PET/MRI, NI-RADS, and Carcinoma of Unknown Primary-AJR Expert Panel Narrative Review.

CT, MRI, and FDG PET/CT play major roles in the diagnosis, staging, treatment planning, and surveillance of head and neck cancers. Nonetheless, an evolving understanding of head and neck cancer pathogenesis, advances in imaging techniques, changing treatment regimens, and a lack of standardized guidelines have led to areas of uncertainty in the imaging of head and neck cancer. This narrative review aims to address four issues in the contemporary imaging of head and neck cancer. The first issue relates to the standard and advanced sequences that should be included in MRI protocols for head and neck cancer imaging. The second issue relates to approaches to surveillance imaging after treatment of head and neck cancer, including the choice of imaging modality, the frequency of surveillance imaging, and the role of standardized reporting through the Neck Imaging Reporting and Data System. The third issue relates to the role of imaging in the setting of neck carcinoma of unknown primary. The fourth issue relates to the role of simultaneous PET/MRI in head and neck cancer evaluation. The authors of this review provide consensus opinions for each issue.

Prognostic impact of copy number alterations and tumor mutational burden in carcinoma of unknown primary.

INTRODUCTION: Chromosomal aberrations are known to drive metastatic spread, but their profile is still elusive in carcinoma of unknown primary (CUP). Therefore, the aim of this study was to characterize the chromosomal aberration pattern in CUP depending on histological and clinical features and to assess its prognostic impact together with chromothripsis, tumor mutational burden (TMB), microsatellite instability (MSI), and mutational profiles as potential prognostic biomarkers. METHODS: Chromosomal aberrations and chromothripsis were detected by methylation-based copy number variation (CNV) analysis, whereas TMB and MSI were calculated based on large next-generation sequencing (NGS) panels. Putative primaries were assigned by consensus between two independent oncologists. RESULTS: CNV losses varied depending on putative primaries and were more abundant in patients harboring TP53 mutations and/or deletions 17p. CNV loss was prognostically adverse in localized CUP treated with surgery and/or radiotherapy, but not in disseminated poor-risk CUP treated with palliative chemotherapy. CNV loss also worsened the prognosis in squamous cell CUP. Chromothripsis was detected in 18/59 (30.5%) patients without prognostic effect. TMB was highest in cases with MSI, squamous cell histology, and with lung, anal or cervical putative primaries. CONCLUSION: Overall, CNV, chromothripsis, TMB, and MSI profiles in CUP are reminiscent of biological characteristics known from other cancer entities without a unifying CUP-specific signature. Markedly, high-level CNV loss is an adverse predictive biomarker in localized but not disseminated chemotherapy-treated CUP. This implies that chromosomal losses drive CUP progression, but also increase susceptibility to chemotherapy, with both effects apparently leveling out in disseminated CUP.

[New strategies for the treatment of carcinoma of unknown primary].

Carcinoma of unknown primary (CUP) is a kind of metastatic tumor whose primary origin cannot be identified after adequate examination and evaluation. The main treatment modality of CUP is empiric chemotherapy, and the median overall survival time is less than 1 year. Compared with immunohistochemistry, novel method based on gene expression profiling have improved the sensitivity and specificity of CUP detection, but its guiding value for treatment is still controversial. The approval of immune checkpoint inhibitors and pan-cancer antitumor agents has improved the prognosis of patients with CUP, and targeted therapy and immunotherapy based on specific molecular characteristics are the main directions of future research. Given the high heterogeneity and unique clinicopathological characteristics of CUP, "basket trial" is more suitable for clinical trial design in CUP.

Detecting undetectable - epidemiology, etiology, and diagnosis of carcinoma of unknown primary - systematic review.

Carcinoma of unknown primary (CUP) is a heterogeneous group of oncological diseases in which it is impossible to determine the primary tumor. The incidence is 3-5% of oncologic patients, but the survival time varies from 6 weeks to 5 months. The diagnostics should begin with a clinical evaluation and basic laboratory tests. For CUP placed in head and neck the positron emission tomography - computed tomography is recommended; pancreatic or lung neoplasms are diagnosed with the computed tomography as well. Recently, the magnetic resonance, especially whole-body diffusion-weighted imaging has been introduced to the imaging panel. The lesion obtained during surgically removed metastases or biopsy material should be histopathological and molecularly examined to define the type of tumor. The basic immunoexpression panel should include cytokeratin-5/6, -7 and -20, EMA, synaptophysin, chromogranin, vimentin and GATA3 and molecular expression of ERBB2, PIK3CA, NF1, NF2, BRAF, IDH1, PTEN, FGFR2, EGFR, MET and CDK6. During the accurate diagnostics enable to classify malignancy of undefined primary origin as provisional CUP or finally confirmed CUP in which the primary place of tumor remains undetectable. The detailed diagnostics should be performed in highly specified centers to establish an accurate diagnosis and to initiate personalized treatment. Majority of patients are diagnosed with adenocarcinoma (70%), undifferentiated carcinoma (20%), squamous cell or transitional cell/uroepithelial carcinoma (5-10%), neuroendocrine tumor (5%) and with minor incidence other histological types, including melanoma.

Extrarenal renal cell carcinoma arising in the kidney proximity but without an identifiable renal primary - an intriguing dilemma: report of three cases and review of the literature.

AIM: To raise awareness of the existence of extrarenal renal cell carcinoma (RCC). METHODS AND RESULTS: We report three patients with extrarenal RCC found in the renal proximity, but unattached to the kidney. None had a history of RCC or an identifiable primary renal neoplasm at the time of the diagnosis and on follow-up. The patients included two males and one female aged 57, 77, and 63 years, respectively. One carcinoma was found in the perirenal tissue adjacent to the adrenal, one involved the adrenal gland, and one was a retroperitoneal mass found within the lymph nodes. Two extrarenal RCCs represented clear-cell RCCs and one was an unclassifiable RCC. No patient had evidence of metastases at presentation and disease progression during the follow-up. This report adds to the literature on this unusual clinical scenario and further supports the concept of extrarenal RCC, which is not a well-recognized clinical phenomenon. We also reviewed other similar reports documenting the absence of identifiable renal primaries in the setting of either disseminated metastatic disease or isolated distant metastases of presumed renal origin. Similarly, some carcinomas of apparent renal derivation have been also identified during a work-up of metastatic carcinomas of unknown primary. CONCLUSIONS: There should be an awareness of this unusual and intriguing clinical scenario that currently lacks a definitive explanation and standardized therapy strategies. Establishing a correct diagnosis may allow treatment with specific targeted therapies in selected clinical cases.

Unusual presentation of HPV-positive squamous cell carcinoma of the nasolacrimal duct as carcinoma of unknown primary.

Most human papillomavirus (HPV)-positive carcinomas of unknown primary (CUP) in the cervical lymph nodes are ultimately found to arise from the oropharynx, which has by far the highest prevalence of HPV-positivity among head and neck tumors. However, HPV is also detected in a subset of tumors from other sites. In this case report, we describe the first reported instance of a lacrimal sac carcinoma presenting as an HPV-positive CUP. A 64-year-old male presented with isolated right-sided neck swelling, found on core biopsy to be HPV-positive squamous cell carcinoma (SCC). Initial diagnostic workup did not reveal a primary site, and he was treated for T0N1M0 oropharyngeal SCC with chemoradiation. Shortly afterwards he developed epiphora and was found to have an FDG-avid lesion along his inferior right orbit. Biopsy revealed HPV-positive SCC, presumed to be the true primary site of his previously diagnosed CUP. He was treated with surgical resection, proton-beam radiation, and carboplatin-paclitaxel. He had an excellent outcome with no evidence of disease 18 months following treatment completion. This case underscores the importance of continued vigilance and thorough investigation for a primary tumor site even when cervical nodal metastases are HPV-positive. While the vast majority of HPV-positive head and neck tumors arise in the oropharynx, other anatomical sites may also harbor HPV-positive malignancies.

Genomic correlates of response and resistance to immune checkpoint inhibitors in carcinomas of unknown primary.

BACKGROUND: Cancers of unknown primary (CUP) are highly aggressive tumours with limited molecular characterization. These tumours can be particularly sensitive to immune checkpoint inhibitors (ICI) by mounting a seemingly more effective anti-tumour immune response. Unlike other tumour lineages, the biological basis and clinical efficacy of ICI in CUP remain largely unknown. MATERIALS AND METHODS: The cBioPortal database was accessed to select eligible cases from the MSK-IMPACTTM Clinical Sequencing Cohort. The tumour cell genomic correlates of response and resistance to ICI in patients with CUP were compared to those with ICI-eligible tumours: cervical cancer, gastric cancer, renal cell carcinoma, hepatocellular carcinoma, non-small-cell lung cancer, melanoma, Merkel cell carcinoma and urothelial bladder cancer. RESULTS: Among a total of 234 patients with CUP, the identified genomic alterations were mainly mutation correlates of resistance to ICI, notably mutations in oncogenic signalling pathways including KRAS, STK11 and EGFR (24.7%, 10.9% and 4.2%, respectively). Compared to other tumours considered eligible for ICI, CUP presents a higher prevalence of alterations in the oncogenic signalling pathways KRAS and STK11. CUP patients treated with ICI had similar median overall survival with and without genomic correlates of response and resistance to ICI. An exploratory analysis showed that patients with TMB >10 mutations had a trend for better outcomes. CONCLUSIONS: A tumour mutation burden >10 mutations per megabase can provide a potential genomic correlate of response to ICI in patients with CUP. Further research is warranted to validate these findings.

Carcinoma of unknown primary origin with isolated adrenal metastasis: a report of two cases.

The adrenal glands are one of the most common sites of malignant tumor metastasis. However, metastatic adrenal carcinoma of unknown primary origin with localized adrenal gland involvement is an extremely rare condition. Herein, we reported two cases of carcinoma of unknown primary origin with isolated adrenal metastasis. In the first case, back pain was the trigger; while in the second case, the triggers were low fever and weight loss. Metabolic abnormalities such as hypertension and obesity were not detected in either case. Neither patient had relevant previous medical histories, including malignancy. However, both had a long-term history of smoking. Systemic imaging studies revealed only adrenal tumors and surrounding lesions. Primary adrenocortical carcinoma was initially suspected, and chemotherapy including mitotane was considered. However, due to difficulty in complete resection of the tumor, core needle tumor biopsies were performed. Histopathological examination of biopsy specimens led to the diagnosis of carcinoma of unknown primary origin with isolated adrenal metastasis. In both cases, additional laboratory testing showed high levels of serum squamous cell carcinoma-related antigen and serum cytokeratin fragment. Malignant lesions confined to the adrenal glands are rare. As in our cases, it could be occasionally difficult to differentiate non-functioning primary adrenocortical carcinoma from metastatic adrenal carcinoma of unknown primary origin localized to the adrenal gland. If the lesion is unresectable and there are elevated levels of several tumor markers with no apparent hormonal excess, core needle tumor biopsy should be considered to differentiate the primary tumor from the metastatic tumor.

Diagnostic approaches to carcinoma of unknown primary of the head and neck.

Squamous cell carcinoma in cervical lymph nodes arising from an undetected primary tumour, termed carcinoma of unknown primary (SCCUP), is a well-recognized clinical presentation within head and neck oncology. SCCUP is a common presentation for patients with human papillomavirus-mediated oropharyngeal cancer (HPV + OPSCC), as patients with HPV + OPSCC often present with smaller primary tumours and early nodal metastasis. Meticulous work-up of the SCCUP patient is central to the management of these patients as identification of the primary site improves overall survival and allows for definitive oncologic resection or more focused radiation when indicated. This review summarizes the comprehensive diagnostic approach to the SCCUP patient, including history and physical examination, methods of biopsy of the cervical lymph node, imaging modalities and intraoperative methods to localize the unknown primary. Novel techniques such as transcervical ultrasound of the oropharynx, narrow band imaging and diagnostic transoral robotic surgery are also discussed.

A case of synchronous high-grade cervical intraepithelial neoplasia and metastatic squamous cell carcinomas of unknown primary in rectum.

We report a case of synchronous high-grade cervical intraepithelial neoplasia (CIN) and metastatic squamous cell carcinomas (SCCs) of unknown primary in the rectum. A 74-year-old woman was diagnosed with CIN3 by biopsy of the uterine cervix. Magnetic resonance imaging showed two masses in the outer rectal wall. They were diagnosed as SCCs by transrectal biopsy from one mass. On surgical treatment, CIN3 and SCCs in the rectum were identified, respectively. Pathological analysis revealed that SCCs were observed in serosa of the rectum, not mucosa, indicating that these tumors were metastatic SCCs. Gene analysis showed HPV31-positive and TP53 mutation in CIN3, and HPV16-positive in rectal SCCs. Pretreatment examination did not detect the primary site of metastatic SCCs in the rectum. We diagnosed the patient with synchronous CIN3 and metastatic SCCs of unknown primary in the rectum. In this case, gene analysis was useful to clarify the relationship between CIN3 and SCCs.

p16 immunohistochemistry for primary tumor detection in HPV-positive squamous cell carcinoma of unknown primary.

PURPOSE: To examine the potential benefit of reevaluation of original slides and p16 immunohistochemistry (IHC) of tonsillectomy specimens for primary tumor identification in cases of human papillomavirus (HPV) positive squamous cell carcinoma (SCC) of the head and neck of unknown primary. MATERIALS AND METHODS: Through a retrospective review, we identified all patients 18 or older who presented at our institution from 2003 to 2015 with histologically confirmed HPV-positive SCC in a cervical lymph node with unidentified primary tumor after initial workup. For patients for whom specimens were available, an expert head and neck pathologist re-reviewed original hematoxylin and eosin (H&E) slides to confirm absence of tumor and performed p16 IHC and deep sectioning of tissue blocks to identify potential tumor foci. RESULTS: Among 735 patient records assessed, 80 were HPV-positive SCC with unknown primary, 28 of which did not have a primary tumor identified, and 20 with original specimens available. Upon re-review of 103 original H&E slides, invasive SCC was identified for 2 patients. Deep sectioning and p16 IHC did not identify additional primary tumors. CONCLUSION: Re-review of original slides by an expert head and neck pathologist, but not p16 staining or deeper H&E sections, was able to identify additional tumors.

Carcinoma of Unknown Primary with EML4-ALK Fusion Response to ALK Inhibitors.

With the advent of next-generation sequencing (NGS) and precision medicine, investigators have determined that tumors from different tissue sources that have the same types of genetic mutations will have a positive response to the same targeted therapy. This finding has prompted us to seek potential therapeutic targets for patients with carcinoma of unknown primary (CUP) using NGS technology. Here, we reported a case of a woman with CUP resistance to chemotherapy. We detected 450 cancer-related gene alterations using three metastatic tumor specimens and found the presence of EML4 exon13 and ALK exon20 fusion. The tumor did respond to crizotinib, a first-generation ALK inhibitor. When her tumor progressed, circulating tumor DNA detection revealed ALK L1196 M and G1269A mutation resistance to crizotinib, but she had a response to brigatinib. This case revealed that NGS technology used to detect the genetic alterations in patients with CUP might be a reliable method to find potential therapeutic targets, although the primary lesion could not always be confirmed. KEY POINTS: This case exemplifies responsiveness to ALK inhibitor in carcinoma of unknown primary (CUP) with EML4-ALK fusion.Next-generation sequencing is an important diagnostic tool to find potential therapeutic targets in CUP.Liquid biopsy may be useful to provide critical information about resistance mechanisms in CUP to guide sequential treatment decision with targeted therapy.

An evaluation of the quality and content of web-based stoma information.

AIM: Although the internet is commonly the first port of call for medical information, it provides unregulated data of variable quality. We aimed to evaluate commonly accessed web-based information on intestinal stomas using validated and novel scoring systems. METHOD: The keywords 'stoma', 'colostomy', 'ileostomy' and 'bowel bag' were entered into the most commonly used internet search engines (Google, Bing and Yahoo). The first ten websites from each search were analysed using the validated Journal of the American Medical Association (JAMA) benchmark criteria and DISCERN scoring systems. A novel stoma-specific score was devised and applied. RESULTS: Forty-three unique websites were identified. The majority (49%) were from nonprofit or governmental agencies and 9% were from commercial entities. The mean total DISCERN score for all websites was 42.4 ± 10.2 (maximum possible score = 75). The mean JAMA and stoma-specific scores were 2.1 ± 1.0 (maximum possible score = 4) and 12.9 ± 6.1 (maximum possible score = 27). The lowest JAMA scores were in the category of attribution, with 70% of websites lacking references for the information provided. A total of 88% displayed disclosure/paid advertiser information. Surgery was described in 67%. An image or diagram was provided in 58% and in 72% a stoma therapist/nurse was mentioned. Information on when to seek medical help was provided in 51%. CONCLUSION: Web-based information on stomas is of variable content and quality. Authorship and information sources are often unclear. Only half provided information on when to seek medical help for complications including high output and dehydration. These findings should be highlighted to patients who utilize the internet to obtain information on stomas.

Genetic characterisation of molecular targets in carcinoma of unknown primary.

BACKGROUND: Carcinoma of unknown primary (CUP) is a metastatic epithelial malignancy in the absence of an identifiable primary tumour. Prognosis for patients with CUP is poor because treatment options are generally limited to broad spectrum chemotherapy. A shift towards personalised cancer management based on mutation profiling offers the possibility of new treatment paradigms. This study has explored whether actionable, oncogenic driver mutations are present in CUP that have potential to better inform treatment decisions. METHODS: Carcinoma of unknown primary cases (n = 21) were selected and DNA was isolated from formalin-fixed paraffin embedded sections prior to amplification and sequencing. Two distinct yet complementary targeted gene panels were used to assess variants in up to 76 known cancer-related genes for the identification of biologically relevant and actionable mutations. RESULTS: Variants were detected in 17/21 cases (81%) of which 11 (52%) were potentially actionable with drugs currently approved for use in known primary cancer types or undergoing clinical trials. The most common variants detected were in TP53 (47%), KRAS (12%), MET (12%) and MYC (12%). Differences at the molecular level were seen between common CUP histological subtypes. CUP adenocarcinomas and poorly differentiated carcinomas harboured the highest frequency of variants in genes involved in signal transduction pathways (e.g. MET, EGFR, HRAS, KRAS, and BRAF). In contrast, squamous cell carcinoma exhibited a higher frequency of variants in cell cycle control and DNA repair genes (e.g. TP53, CDKN2A and MLH1). CONCLUSION: Taken together, mutations in biologically relevant genes were detected in the vast majority of CUP tumours, of which half provided a potentially novel treatment option not generally considered in CUP.